Human papillomavirus (HPV) infection of the cervix is usually self-limiting, but it can progress to cervical cancer, which kills ~273,500 women each year worldwide. Even in the United States, cervical cancer is the third most common cause of cancer death in women aged 15-34 ranks fourth for average years of life lost, and it disproportionately affects minority groups and women of low socioeconomic status. Epidemiologic studies suggest that heritability accounts for ~27% of the variation in the risk for cervical tumors. Through a candidate gene approach that used family-based controls, we have identified variations in the host genome that associate with disease progression. Many associations are stronger in a subgroup of women with invasive cervical cancer (ICC) who are infected by the high-risk HPV types 16, 18, and related subtypes. To accelerate the discovery of genetic factors involved in the development of cervical cancer, we propose three specific aims. Aim 1 will validate candidate genes involved in cervical carcinogenesis and identify novel single nucleotide polymorphisms (SNPs) of disease, using a genome-wide association study. In stage 1 of this Aim, we will use a case-control sample of 500 unrelated Caucasian women with ICC (collected previously) and 2000 Caucasian female population controls identified from publicly available genotyping control databases. In stage 2, we will investigate a second independent case-control set (similar to the first) to validate 1000 SNPs identified from the list of well-motivated candidate genes and the top ~5000 hits from the genome-wide association study. In the statistical analysis, we will combine the stage 1 and stage 2 data. In Aim 2 we will explore interactions among susceptible SNPS and perform subgroup analysis among the 1000 cases and 4000 controls. Heterogeneity will be explored in various subsets of cases such as HPV type, age at diagnosis, and histology. The SNPs that show the most significant associations with ICC will be validated in other minority groups in Aim 3, using DNA samples from African American family-based trios of ICC and in situ disease and a cohort of Hispanic women with ICC/CIN 3. This study will enable us to validate markers of susceptibility to ICC while using available resources economically. Determining how variations in host DNA influence women's vulnerability to cervical cancer is important for several reasons. First, such studies could uncover genetic markers for identifying women who are at high risk for developing the disease. Second, they could reveal how the body defends itself after HPV infection, which might suggest new strategies for vaccine design or drug development. Finally, a database and corresponding blood samples and tumors from cases of ICC and DNA from family members would be an invaluable resource for future studies.